OncoArendi Therapeutics SA , Żwirki i Wigury 101, 02-089 Warsaw, Poland.
Department of Immunology, Medical University of Warsaw , 1A Banacha Str., 02-097 Warsaw, Poland.
J Med Chem. 2018 Feb 8;61(3):695-710. doi: 10.1021/acs.jmedchem.7b01051. Epub 2018 Jan 11.
This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase inhibitor (IC values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150× against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity. Therapeutic efficacy of compound 7f in the clinically relevant aeroallergen-induced acute asthma model in mice provides a rationale for developing AMCase inhibitor for the treatment of asthma.
本文重点介绍了我们在鉴定强效、选择性和有效的酸性哺乳动物几丁质酶 (AMCase)抑制剂方面的工作。通过对几种与人类几丁三糖酶（hCHIT1）结合的抑制剂的 X 射线分析进行合理设计，确定了化合物 7f 为一种高效的 AMCase 抑制剂（对人源和鼠源酶的 IC 值分别为 14 和 19 nM），且对 mCHIT1 的选择性（>150 倍）较高，具有良好的 PK 性质。该化合物以 30mg/kg po 剂量每日给药一次，在 HDM 诱导的小鼠变应性气道炎症中表现出显著的抗炎疗效，减少 BALF 中的炎症细胞浸润和血浆中的总 IgE 浓度，这与几丁质酶活性的降低相关。化合物 7f 在临床上相关的变应原诱导的急性哮喘模型中的治疗效果为开发用于治疗哮喘的 AMCase 抑制剂提供了依据。
